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. 2022 Jun 5;14(11):2353. doi: 10.3390/nu14112353

Table 1.

Summary of clinical studies and trials investigating the relation between vitamin D and eye diseases.

Type of Study/ClinicalTrials.gov Identifier/Phase (If Specified) Participants/Enrollment/DeMographics of Population Method Findings Ref
Age-related macular degeneration
Case-control study 161 neovascular AMD cases from two university hospitals and 369 population-based control subjects from a cohort study Brief-type self-administered questionnaire on diet history, which required respondent recall of the usual intake of 58 foods during the preceding month Logistic regression analysis showed that low intake of vitamin D was associated with neovascular AMD (Trend p < 0.002) [32]
Clinical case–control pilot study 96 Korean patients: 30 with late AMD, 32 with early AMD, and 34 normal controls Measurement and comparison serum 25(OH)D levels Serum vitamin D deficiency may elevate the risk of early (OR = 3.59; 95%CI 0.95–13.58; p = 0.06) and late AMD (OR = 3.61; 95%CI 1.04–12.51; p = 0.043) and may also be associated with subretinal fibrosis [33]
Cross-sectional study 95 patients with exudative AMD and 95 healthy age- and sex-matched controls Measurement and comparison serum 25(OH)D levels Significant lower 25(OH)D levels in patients with AMD compared to the control subjects (p = 0.042) [34]
Population-based, cross-sectional study 17,045 Korean subjects older than 40 years Standardized interviews, evaluation of blood 25-(OH)D levels and comprehensive ophthalmic examinations Inverse association between high level of blood 25(OH)D with late AMD in men but not women [35]
Population-based, prospective analysis 1225 (196 African American; 1029 Caucasian) Evaluation of blood 25-(OH)D levels and ophthalmic examinations Logistic regression showed that high 25(OH)D concentrations (>70 nM) may be associated with reduced odds of incident early AMD [36]
Cross-sectional study 1045 members with AMD and 8124 without AMD Comparison of serum 25(OH)D levels between the two groups No association was detected between 25(OH)D levels and the presence of AMD [37]
Population-based study 697 (264 men, 433 women) Assessment of associations between AMD and plasma 25(OH)D status using generalized estimating equation logistic regressions Lack of specific role of vitamin D in AMD [38]
Meta-analysis Literature database Identification of the association between serum vitamin D levels and AMD risk Lack of evidences to inverse association between serum vitamin D levels and any stages and subtypes of AMD risk [39]
Population-based, cross-sectional study 2137 without AMD, 2209 with early AMD, 150 with late AMD, of whom 104 with neovascular AMD Comparison of serum 25(OH)D levels No linear association between 25(OH)D and early or late AMD or neovascular AMD [40]
Cross-sectional study 9734 (7779 Caucasians, 1955 African American Secondary data analysis of already existing data from the AtherosclerosisRisk in Communities Study Lack of association between vitamin D status and early AMD [41]
Pilot study Treatment group with 15 subjects and control, group with 15 subjects Measurement and comparison serum 25(OH)D levels Lack of association between vitamin D status and AMD [42]
Systematic review and meta-analysis Literature database Identification of the association between serum vitamin D levels and AMD risk Lack of a definitive association between serum 25(OH)D and AMD risk [43]
Nationwide, double-blind, placebo controlled randomized clinical trial 25,871 Supplementation of 2000 IU/day for a median 5.3 years Lack of vitamin D supplementation on AMD incidence and progression [45]
Diabetic retinopathy
Cross-sectional study 30 subjects with DR and 30 subjects without DR Measurement and comparison serum 25(OH)D levels Lower levels of serum 25(OH)D in DR [47]
Cross-sectional study 1790 Measurement and comparison serum 25(OH)D levels Association between DR and prevalence of vitamin D deficiency [48]
Population-based cross-sectional study 2113 participants aged ≤ 40 years Evaluation of blood 25-(OH)D levels and ophthalmic examinations Inverse association of blood 25(OH)D levels with any DR and proliferative DR only in men [49]
Meta-analysis Literature database Identification of the association between serum vitamin D levels and DR Statistically significant association between vitamin D deficiency and DR [50]
Retrospective study 3054 Asian Indians with type 2 diabetes mellitus Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association between lower serum 25(OH)D and increased severity of DR. Association between vitamin D deficiency and two-fold increased risk for proliferative DR [51]
Cross-sectional study 638 patients with type 2 diabetes mellitus Evaluation of blood 25-(OH)D levels and clinical examinations Vitamin D deficiency is considered as a risk factor for DR [52]
Cross-sectional study 4767 diabetic patients Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association between lower serum 25(OH)D and higher prevalence of DR in middle-aged and elderly diabetic adults [53]
Clinic-based, cross-sectional study 221subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Diabetic subjects, especially those with PDR, have lower 25(OH)D levels than those without diabetes [54]
Hospital-based cross-sectional study 889 type 2 diabetic patients with or without DR Evaluation of blood 25-(OH)D levels and clinical examinations Vitamin D deficiency is significantly associated with risk of proliferative DR [55]
Cross-sectional study 517 subjects aged 8–20 years with type 1 diabetes mellitus Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association between the vitamin D deficiency and increased prevalence of DR in young people with type 1 diabetes mellitus [56]
Meta-analysis Literature database Identification of the association between serum vitamin D levels and DR Association between the vitamin D deficiency and increased risk of DR patients with type 2 diabetes mellitus [57]
Retrospective study 182 with type 1 diabetes mellitus Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association between the vitamin D deficiency and increased prevalence of DR in patients with type 1 diabetes mellitus [58]
Cross-sectional study 460 patients with type 2 diabetes mellitus (median age 55.2 years; age range, 30–90 years; 227 male and 233 female) and 290 non-diabetic control subjects (median age 46.1 years; age range, 30–85 years; 151 male and 139 female) Evaluation of blood 25-(OH)D, 1,25(OH)2D, 24,25(OH)2D levels and ophthalmic examinations Association between vitamin D3 metabolites and DR, whereas lack of these dependence for total vitamin D levels [60]
Tertiary care center based cross-sectional study Diabetes mellitus without DR (24), non-proliferative DR (24), proliferative DR (24) and controls (24) Evaluation of blood 25-(OH)D levels and ophthalmic examinations Serum vitamin D levels of ≤ 18.6 ng/mL is marker for proliferative DR [59]
Systematic review and meta-analysis Literature database Identification of the association between VDR gene polymorphisms and DR susceptibility The VDR FokI gene variant is associated with DR [66]
Meta-analysis Literature database Identification of the association between VDR gene polymorphisms and DR susceptibility The VDR BsmI, ApaI and FokI gene variants are associated with DR susceptibility [4]
Optic neuritis
Placebo-controlled randomized clinical trial 52 patients with confirmed unilateral ON aged 15–38 years and low serum 25(OH)D levels Supplementation of 50,000 IU/week vitamin D3 or placebo for 6 months Adding vitamin D to routine disease therapy had no significant effect on the thickness of RNFL or macula in patients with ON [70]
Cross-sectional study 164 patients with monosymptomatic ON and 948 patients with MS Evaluation of blood 25-(OH)D levels and clinical examinations Lack of correlation between levels of vitamin D and ON severity [71]
Doubleblind, randomized, placebo-controlled pilot clinical trial 30 patients with ON Supplementation of 50,000 IU/week vitamin D3 or placebo for 12 months Administration of vitamin D3 by patients with ON and low serum 25-(OH)D levels may delay the onset of a second clinical attack and the subsequent conversion to MS [72]
Cross-sectional study 74 patients with MS Evaluation of blood 25-(OH)D levels and ophthalmic examinations Lack of association between vitamin D deficiency and thinning of RNFL or macular volume in MS eyes unaffected by ON [73]
Retinal vein occlusion
Pilot study 40 patients with RVO and 40 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Significant lower levels of serum 25(OH)D in RVO as compared to age matched controls [77]
Case control study (NCT01793181) 79 patents with CRVO and 144 control subjects Evaluation of blood 25-(OH)D levels and clinical examinations Patients under 75 years with CRVO had significantly lower 25(OH)D levels compared to the control [78]
Myopia
Study based on Korea National Health and Nutrition Examination Survey 2038 Korean adolescent aged 13 to 18 years Evaluation of blood 25-(OH)D levels and ophthalmic examinations Decreased serum 25(OH)D level was associated with myopia prevalence in Korean adolescents [81]
Study based on the Western Australian Pregnancy Cohort (Raine) Study 221 patients with myopia, 725 nonmyopic subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Decreased serum 25(OH)D level was associated with myopia [82]
Study based on Korea National Health and Nutrition Examination Survey 15,126 Korean aged 20 years or older Evaluation of blood 25-(OH)D levels, daily sun exposure time and ophthalmic examinations Low serum 25(OH)D levels and shorter daily sun exposure time is independently associated with a high prevalence of myopia [83]
Population-based prospective cohort study 2666 children aged 6 years Evaluation of blood 25-(OH)D levels, daily sun exposure time and ophthalmic examinations Low serum 25(OH)D is associated with axial length and risk of myopia in young children [84]
Systematic review and meta-analysis Literature database Identification of the association between serum vitamin D levels and myopia Lower 25(OH)D is associated withincreased risk of myopia [85]
Study based on Korea National Health and Nutrition Examination Survey 25,199 subjects aged ≥ 20 years Evaluation of blood 25-(OH)D levels and ophthalmic examinations Serum 25(OH)D level was inversely associated with myopia in adults [86]
Study based on the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort Children participating in ALSPAC Evaluation of total vitamin D, vitamin D3, vitamin D2 levels, time outdoors and ophthalmic examinations Vitamin D may serve as biomarker for time spent outdoors without association with myopia [87]
Mendelian randomization study based on meta-analysis of refractive error genome-wide association study 37,382 and 8376 adult participants of European and Asian ancestry, respectively Identification of the association between serum vitamin D levels and myopia Contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero [88]
Study based on the Busselton Healthy Ageing Study Community-based cohort of adults aged 46 to 69 years Evaluation of blood 25-(OH)D levels and ophthalmic examinations There was no substantial association between 25(OH)D levels and spherical equivalent or odds of myopia [89]
Prospective, cross-sectional study Children born prematurely between January 2010 and December 2011 when they reached school age between April 2017 and June 2018 Evaluation of blood 25-(OH)D levels and ophthalmic examinations More time spent outdoors is associated with lower odds of myopia. The serum 25(OH)D concentration is not associated with myopia [90]
Case-control study 457 myopic male cases and 1280 emmetropic male controls Evaluation of blood 25-(OH)D levels and ophthalmic examinations The myopia is not related to neonatal vitamin D status [91]
Cross-sectional, population-based random study 4166 participants 65 years and older Evaluation of vitamin D3 levels, time outdoors and ophthalmic examinations Increased UVB exposure is associated with reduced myopia [92]
Systematic review and meta-analysis Literature database Identification of the association between time spent outdoor and myopia Increased time outdoors is effective in preventing the onset of myopia as well as in slowing the myopic shift in refractive error. Outdoor time is not effective in slowing progression in eyes that were already myopic. [93]
Non-infectious uveitis
Prospective, multicenter, observational cohort study 360 Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) Evaluation of blood 25-(OH)D levels and clinical examinations Vitamin D deficiency is associated with the risk for uveitis in juvenile idiopathic arthritis [113]
Case-control study 558 patients with non-infectious uveitis and 2790 control subjects Evaluation of blood vitamin D levels and clinical examinations Association between hypovitaminosis D and non-infectious uveitis [114]
Case-control study 100 patients with non-infectious anterior uveitis and 100 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Lower vitamin D levels are associated with an increased risk of non-infectious anterior uveitis [115]
Observational case–control study 20 patients with acute anterior uveitis and 100 consecutive, age and sex matched healthy subjects without any ocular or systemic diseases Evaluation of blood 25-(OH)D levels and ophthalmic examinations The patients with acute anterior uveitis have decreased 25(OH)D level [116]
Prospective case-control study 74 patients with active uveitis and 77 patients with inactive uveitis Evaluation of blood 25-(OH)D levels and ophthalmic examinations Active uveitis is associated with significantly lower serum 25(OH)D levels than inactive uveitis [117]
Retrospective case-control study 333 patients with uveitis and 329 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Hypovitaminosis D is associated with increased risk of non-infectious uveitis [118]
Monocentric retrospective cohort study 59 patients with uveitis Evaluation of blood 25-(OH)D, 1,25,(OH)D levels and ophthalmic examinations High 1,25(OH)2D/25(OH)D ratio is useful for the diagnosis of sarcoidosis-related uveitis [119]
Vogt-Koyanagi-Harada disease
Case-control study 25 patients with VKHD and 16 health subjects Evaluation of blood 1,25(OH)2D levels and clinical examinations Reduced expression of 1,25(OH)2D may be involved in the development of VKHD [122]
Case-control study 39 patients with VKHD and 50 control subjects Sequencing analysis of the VDR, CYP24A1, CYP27B1 and CYP2R1 genes (involved in the metabolism of vitamin D) Detection of potentially pathogenic sequence variant in CYP2R1 may cause VKH in a subset of patients [123]
Glaucoma
Case-control and an intervention study 39 received vitamin D supplements, 39 received placebo and 42 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations; Supplementation of 40000 IU/week vitamin D3 or placebo for 6 months for participants with low vitamin D level No difference between IOP and low/high serum 25(OH)D levels. No significant difference between experimental and control groups [126]
Cross-sectional study 6094 Evaluation of blood 25-(OH)D levels and ophthalmic examinations Vitamin D deficiency Seems to be independent risk factor for open-angle glaucoma [127]
Case-control study 150 patients with glaucoma and 164 health subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma [128]
Cross-sectional and observational study 20 patients with glaucoma and 20 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Serum Vitamin D level is statistically significantly lower in glaucoma [129]
Case-control study 73 with glaucoma and 71 age-matched control subjects Evaluation of blood calcitriol levels and ophthalmic examinations Decreased calcitriol levels in glaucoma [130]
Case-control study 357 patients with glaucoma and 178 control subjects of African descent Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association between the level of 25-(OH)D and glaucoma severity [131]
Cataract
Case-control study 325 patients with cataract and 385 control subjects Evaluation of blood 25(OH)D levels and ophthalmic examinations Association of Serum 25(OH)D deficiency and age-related cataract [134]
Observational cross-sectional study based on Korea National Health and Nutrition Examination Survey 18804 Evaluation of blood 25(OH)D levels and ophthalmic examinations The age-related cataract risk is decreased in men with higher serum 25(OH)D levels [135]
Case control study 37 patients with cataract and 53 health subjects under the age of 60 years Evaluation of blood 25(OH)D levels and ophthalmic examinations Vitamin D deficiency is associated with early age-related cataract [136]
Study based on the Carotenoid Age-Related Eye Study 1278 Evaluation of blood 25(OH)D levels and ophthalmic examinations Inverse association between serum 25(OH)D and nuclear cataract in women younger than 70 years [137]
Study based on Korea National Health and Nutrition Examination Survey 16,086 (7093 males and 8993 females) adults aged 40 years or older Evaluation of blood 25(OH)D levels and ophthalmic examinations Serum 25(OH)D levels are inversely associated with the risk of nuclear cataract [138]
Retrospective chart review study 195 Evaluation of blood 25(OH)D levels and ophthalmic examinations Vitamin D deficiency is associated with posterior subcapsular cataract [139]
Prospective hospital-based cross-sectional study 79 patients with posterior subcapsular cataract or age-related cataract without posterior subcapsular cataract component Evaluation of blood vitamin D levels and ophthalmic examinations Posterior subcapsular cataract is not associated with vitamin D insufficiency [140]
Prospective study 87 patients with senile cataract and 49 patients with diabetic cataract Evaluation of blood and aqueous humor 25(OH)D levels and ophthalmic examinations Higher 25(OH)D level in aqueous humor is associated with diabetic cataract [141]
Scleritis
Retrospective case-control study 103 patients with scleritis and 329 control subjects Evaluation of blood 25(OH)D levels and ophthalmic examinations Hypovitaminosis D is associated with increased risk of scleritis [118]
Dry eye syndrome
Systematic review and meta-analysis Literature database Identification of the association between vitamin D level and DES Significantly lowered serum level of 25(OH)D in DES [147]
Systematic review and meta-analysis Literature database Identification of the association between vitamin D level and DES Vitamin D deficiency is associated with severity of DES [148]
Systematic review and meta-analysis Literature database Identification of the association between vitamin D level and DES Vitamin D deficiency may be a risk factor for DES [149]
Study based on Korea National Health and Nutrition Examination Survey 17,542 adults (7434 men and 10,108 women) aged 19 years Evaluation of blood 25(OH) levels and clinical examinations Decreased serum 25(OH)D levels and inadequate sunlight exposure are associated with DES. The vitamin D supplementation may be useful in DES treatment [150]
Cross-sectional study 47 patients with evaporative DES and 33 control subjects Evaluation of blood/tear 25(OH) levels and clinical examinations Significantly lowered tear level of 25(OH)D in DES [151]
Observational study 34 patients with vitamin D deficiency and 21 control subjects with normal level of vitamin D Evaluation of blood/tear 25(OH) levels and ophthalmic examinations Vitamin D deficiency results in the TBUT and Schirmer’s test values [152]
Single-center, cross-sectional observational study 30 patients with vitamin D deficiency and 30 control subjects with normal level of vitamin D Evaluation of blood/tear 25(OH) levels and ophthalmic examinations Vitamin D deficiency is associated with tear hyperosmolarity and tear film dysfunction [153]
Retrospective observational study 79 patients (22 male and 57 female) Evaluation of blood 25(OH)D levels and ophthalmic examinations Tear break-up time and tear secretion were correlated with serum vitamin D levels [154]
Study based on Korea National Health and Nutrition Examination Survey 16,396 participants aged >19 years Evaluation of blood 25(OH)D levels and ophthalmic examinations There is no association between 25(OH)D levels and DES [155]
Study based on Study Group for Environmental Eye Disease 740 subjects (253 men and 487 women) Evaluation of blood 25(OH)D levels and ophthalmic examinations There is no association between 25(OH)D levels and DES [156]
Observational study 105 (21 men and 84 women) with mean serum 25(OH)D level of 10.52 ± 4.61 ng/mL Evaluation of blood 25-(OH)D levels and ophthalmic examinations; Intramuscular injection of 200,000 IU cholecalciferol for participants with deficient or insufficient vitamin D level The supplementation of vitamin D is effective and useful in the treatment of patients with DES [157]
Retrospective, observational study 116 patients with DES Evaluation of blood 25-(OH)D levels and ophthalmic examinations The effect of topical artificial tears and hyaluronate in the therapy of DES is dependent on serum 25(OH)D levels. The cholecalciferol supplementation enhanced the efficacy of topical DES treatment [158]
Case-control study 64 patients with DES and 51 control subjects Identification of the association between VDR gene polymorphisms and DES susceptibility Two polymorphisms (Foklrs2228570 and Apal-rs7975232) in the VDR gene are 1.72 and 1.66 times more likely in DES-patients than in control, respectively [22]
Vernal keratoconjunctivitis
Case-control study 47 patients with VKC, aged between 5 and 12 years, and 63 healthy children Evaluation of blood 25-(OH)D levels and ophthalmic examinations Children affected by VKC have lower vitamin D levels. Significant correlation between the disease severity and the level of vitamin D [161]
Prospective, observational, caseـcontrol study 39 patients with VKC (21 men and 18 women) and 32 health subjects (19 men and 13 women) with the mean age of 18.38 ± 8.83 and 21.6 ± 9.43, respectively Evaluation of blood 25-(OH)D levels and ophthalmic examinations Patients with VKC have lower vitamin D levels; No significant reverse correlation between the disease severity and the level of vitamin D [162]
Prospective, single-centered, observational, case–control study 29 children with VKC and 62 health children Evaluation of blood 25-(OH)D levels and ophthalmic examinations Children with VKC should be evaluated for vitamin D deficiency, which might occur secondary to sun avoidance [163]
Observational study 242 children with VKC Evaluation of blood 25-(OH)D levels and ophthalmic examinations Ocular treatment using immunomodulatory eye drops results in an improvement in 25OHD serum levels [165]
Keratoconus
Prospective, single-centered, observational case-control study 100 patients with keratoconus and 100 health control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Patients with KC had reduced serum vitamin D levels compared to age- and sex-matched healthy controls [170]
Cross-sectional study 100 patients with keratoconus and 100 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Lower serum 25(OH)D was found in patients with keratoconus compared to the control group [171]
55 patients with keratoconus (28 progressive and 27 non-progressive) and 30 age- and sex-matched control subjects Evaluation of blood vitamin D levels and ophthalmic examinations Serum vitamin D evaluation in patients with keratocnous at onset and follow-up examinations may help to predict the course of the disease [172]
Pterygium
Study based on Korea National Health and Nutrition Examination Survey 19,178 participants aged 30 years Evaluation of blood 25-(OH)D levels and ophthalmic examinations Positive association between blood 25(OH)D levels and pterygium [179]
Prospective study 63 patients with pterygium and 58 control subjects Evaluation of blood 25-(OH)D levels and ophthalmic examinations Increased level of blood 25(OH)D in only male subjects with pterygium and in those with more outdoor activity [180]
Population-based, cross-sectional study based on Korea National Health and Nutrition Examination Survey 12,258 adults (aged ≥ 19 years) Evaluation of blood 25-(OH)D levels and ophthalmic examinations Association of daily sun exposure and serum 25(OH)D levels in pterygium [178]
Case-control study 35 (21 male, 14 female) patients with unilateral pterygium and 25 (18 male, 7 female) healthy controls Evaluation of blood/tear vitamin D levels and ophthalmic examinations Tear fluid and serum vitamin D concentrations do not have a role in pterygium pathogenesis [181]
Cross-sectional study 50 patients with pterygium and 50 control subjects Identification of the VDR gene expression in pterygium; Identification of the VDR gene polymorphisms and DES susceptibility VDR expression is increased in thepterygium tissue compared to the adjacent healthy tissue. No significant difference in BsmI, FokI and TaqI polymorphisms in comparison to the control [182]
Thyroid eye disease
Retrospective chart review 35 patients with TED Evaluation of blood 25-(OH)D levels and clinical examinations 20% prevalence of vitamin D deficiency in TED [188]
Retrospective case-control study 89 TED patients and 89 Graves disease patients without TED, and 2 healthy control groups matched 4:1 to the cases; 356 health control patients matched to the TED group and 356 health control patients matched to the Graves disease Evaluation of blood 25-(OH)D levels and clinical examinations Low serum vitamin D is associated with TED diagnosis [189]
Case-control study 108 patients with thyroid-associated orbitopathy and 130 health control subjects (Caucasian Polish origin) Identification of the VDR gene polymorphisms and thyroid-associated orbitopathy susceptibility C allele of rs2228570 VDR gene polymorphism may contribute to the development of thyroid-associated orbitopathy [190]
Benign essential blepharospasm
Prospective study 50 patients with BEB and 22 health subjects Evaluation of blood 25-(OH)D levels and clinical examinations Serum vitamin D levels showed a moderate negative correlation with disease severity [194]
Retrospective case-control study 20 patients with BEB and 20 age- and gender-matched health subjects Evaluation of blood 25-(OH)D levels and clinical examinations Strong negative correlation between disease severity and reduced 25(OH) vitamin D in patients with BEB [196]